We hear from Dr Agata Rozanka, part of Professor Lako’s team at Newcastle University, about the CHECT-funded retinoblastoma project they have just completed, and what the next steps will be.
Although there are many successful treatments for retinoblastoma, these treatments can leave young patients with varying degrees of visual impairment. This is because, in addition to causing the death of retinoblastoma cells, the treatments can also affect the neighbouring retina and pigmented cell layer (called RPE), both of which are essential for good vision.
This project aimed to improve treatments and reduce negative side effects, by developing a laboratory model of retinoblastoma on which new and existing treatments could be tested.
The team developed a lab model of Rb, by converting a retinoblastoma patient’s blood cells into stem cells. These cells were then coaxed into cell aggregates or clumps, named organoids. We have also, established an RPE model from the healthy stem cells (Figure 1).
Figure 1. Workflow of our experimental design.
The retinoblastoma-like organoids were compared to healthy organoids. Doing this confirmed that the retinoblastoma-like organoids had the key features of Rb tumours, such as cell multiplication. This uncontrolled growth of certain cells was narrowed down to a specific cell type that co-builds the retina (Figure 2).
Figure 2. Diagram showing two cell types: cone precursors (green) and proliferating cone precursors (red), in healthy and retinoblastoma-like organoids. The graph shows the significant increase in a certain type of cell called ‘proliferating (Ki67 positive) photoreceptors (RXRγ)’ in retinoblastoma-like organoids.
The team selected three widely used chemotherapy drugs, which were applied to the retinoblastoma organoids in different doses. The data shows that these drugs are effective, in different doses, at eliminating the starting cell type that results in the development of retinoblastoma (proliferating cone precursors as shown in Figure 2). This demonstrates the value of the organoid model as a tool for testing new drugs. Using an additional model developed in our lab, of healthy RPE cells, we have also examined the amount of damage the three selected chemotherapy drugs cause to this cell layer.
The data show that the drugs do indeed cause some damage to the RPE, which suggests that great care has to be taken to make sure the chemotherapy drugs are delivered directly to the Rb tumour, without damaging the healthy RPE, which could cause varying degrees of vision loss.
Altogether, the data demonstrate that these organoid models are useful tools for screening new treatment drugs and for further retinoblastoma analysis. This will help to shape treatment strategies of the future, such as new combinations of drugs, and testing different dosages to effectively treat retinoblastoma tumours while minimising any damage to vision. The models developed through the course of this research project will be used to test new and existing drugs to increase the success of local injections of chemotherapy into the eye. Using organoids in this way means we no longer have to keep going back to test on enucleated tissue and provides an effective way to test the effectiveness of new Rb treatments in the lab, prior to human trials.
For the next stage of our research, we have drawn up a list of drugs that have the potential for selective targeting. Using the new organoid tools, we can then shortlist those that are most effective at treating retinoblastoma, while minimising any damage caused to the healthy retinal cells of young patients, and so preserving as much sight as possible.
You can learn more about our research over the on research section of our website.